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Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma.

Daqi Li·Gaoyuan Cui·Kailin Yang·Chenfei Lu·Yuhan Jiang·Le Zhang·Qiulian Wu·Deobrat Dixit·Zhe Zhu·Ryan C Gimple·Danling Gu·Jiancheng Gao·Qiankun Lin·Hang Yu·Zhumei Shi·Yun Chen·Qianghu Wang·Guangfu Jin·Fan Lin·Junfei Shao·Qigang Zhou·Chong Liu·Chaojun Li·Yongping You·Nu Zhang·Junxia Zhang·Xu Qian·Qian Zhang·Jeremy N Rich·Xiuxing Wang
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Abstract

Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4-MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.

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GlioblastomaHumansAnimalsMembrane ProteinsLactic AcidSignal TransductionTumor MicroenvironmentMiceMonocarboxylic Acid TransportersNeoplastic Stem CellsBrain NeoplasmsCell Line, Tumor5'-NucleotidaseTumor-Associated MacrophagesNucleotidyltransferasesMacrophagesSymportersCell ProliferationImmune Checkpoint InhibitorsFemaleSTING ProteinCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseJournal Article

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Daqi Li, Gaoyuan Cui, Kailin Yang, Chenfei Lu, Yuhan Jiang, Le Zhang, Qiulian Wu, Deobrat Dixit, Zhe Zhu, Ryan C Gimple, Danling Gu, Jiancheng Gao, Qiankun Lin, Hang Yu, Zhumei Shi, Yun Chen, Qianghu Wang, Guangfu Jin, Fan Lin, Junfei Shao, Qigang Zhou, Chong Liu, Chaojun Li, Yongping You, Nu Zhang, Junxia Zhang, Xu Qian, Qian Zhang, Jeremy N Rich, Xiuxing Wang. 2026-01-06. Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma.. https://doi.org/10.1038/s41556-025-01839-y

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